LDL-pheresis is a newly developed technique that permits the specific removal of low density lipoprotein (LDL) from the circulatory system. By combining continuous plasma-pheresis with extracorporeal immunoadsorption of LDL on columns of anti-LDL Sepharose, 60-80 percent of plasma LDL can be selectively removed from patients in a 2-3 hour procedure. Only plasma exchange and LDL-pheresis are capable of reducing total plasma cholesterolyl by 50 percent or more. Plasma exchange removes all proteins from the plasma, including high-density lipoproteins (HDL), while LDL-pheresis returns all plasma proteins to the patient except LDL, thus conserving HDL and avoiding the expense of plasma protein substitution, with its related hazards. We propose to define the effectiveness and limitations of LDL-pheresis as a means of cholesterol lowering and to explore thoroughly the effects of LDL-removal on LDL metabolism and sterol homeostasis. A group of outpatients with documented coronary heart disease will be treated by LDL-pheresis alone and then in combination with a drug (nicotinic acid, cholestyramine, or mevinolin) to judge the effectiveness of cholesterol lowering under various conditions. The effect of LDL lowering on LDL metabolism will be investigated in all treatments by 125I-LDL turnover studies carried out in the steady state before and in the nonsteady state after LDL-pheresis. The data obtained will be used to develop models of LDL rebound kinetics. Preliminary studies indicating that increased cholesterol synthesis occurs during the LDL rebound will be continued and related to measurement of cholesterol efflux. A second patient group, all with familial hypercholesterolemia, will be studied as in- and outpatients to determine whether or not removal of plasma LDL by LDL-pheresis causes net cholesterol efflux from tissue stores in the short term and net depletion of whole body cholesterol over the long term. Pool size measurements, carried out at baseline and after a 2 years' program of repeated LDL-phereses, will establish whether total exchangeable cholesterol pools have been reduced by this Procedure. The rate of re-accumulation of excess stores of cholesterol will be determined by carrying out a third pool size measurement one year after LDL-pheresis has been discontinued.